Infertility, overpopulation and reproductive disorders are major problems facing Society. This proposal focuses on integration of the three great communication systems in the body - the endocrine, the central nervous and the immune systems - and how this impacts the ovulatory cycle of females. The importance of the endocrine and nervous systems in orchestrating the events of the cycle, and in coordinating reproductive processes with the external environment, has long been recognized. Only recently, however, has the role of the immune system come to the forefront. The immune system elaborates a cascade of neural and humoral signals when challenged by inflammatory stimuli and invasion of the body by foreign organisms. Through mechanisms not fully understood, these immune signals powerfully inhibit reproduction. The broad objective of this research is to determine how an immune challenge impacts the neuroendocrine axis to inhibit the ovarian cycle. The general approach is to integrate current knowledge of the physiologic basis for the estrous cycle of sheep with observed changes in neuroendocrine activity following a standardized immune challenge (endotoxin). In this manner, processes critical to reproductive suppression will be pinpointed. Specific Aim 1 elucidates the influence of an immune challenge on the estrous cycle. This will be achieved by assessing the effects endotoxin on progression of the hormonal events of the follicular and luteal phases of the cycle, and by assessing the influence of ovarian steroids on neuroendocrine responses to an immune challenge. Specific Aim 2 addresses mechanisms whereby an immune challenge inhibits pulsatile secretion of GnRH and LH. This includes investigations directed at both the hypothalamic level (secretion of GnRH into pituitary portal blood) and the pituitary level (responsiveness to GnRH). Specific Aim 3 focuses on the impact of an immune challenge on surge secretion of GnRH and LH. This includes how an immune challenge impacts activation of estradiol receptive neurons in the hypothalamus, the transduction of the surge inducing signal to the GnRH neuronal network, and the actual surge processes of GnRH and LH release. The research incorporates a variety of approaches including monitoring secretion of hormones from the hypothalamus, the pituitary and the ovary, and immunocytochemical analysis of hypothalamic systems known to be crucial to reproduction. The health-related relevance of this work is that it will provide an in depth integrated analysis of how immune challenges, infectious and inflammatory disease, physical injury and trauma, and a variety of noxious stimuli lead to reproductive failure.